scholarly journals PI3Kδ inhibition prevents IL33, ILC2s and inflammatory eosinophils in persistent airway inflammation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Sorif Uddin ◽  
Augustin Amour ◽  
David J. Lewis ◽  
Chris D. Edwards ◽  
Matthew G. Williamson ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Goblet Cell ◽  
House Dust ◽  
House Dust Mite ◽  
Inflammatory Responses ◽  
Lymphoid Cells ◽  
Antibody Treatment ◽  
Dust Mite ◽  
Group 2 ◽  
Goblet Cell Metaplasia

Abstract Background Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group 2 innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. Results Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. Conclusions Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.

scholarly journals PI3Kδ Inhibition Prevents IL33, ILC2s and Inflammatory Eosinophils in Persistent Airway Inflammation

2021 ◽  
Author(s):  
Sorif Uddin ◽  
Augustin Amour ◽  
David J Lewis ◽  
Chris D Edwards ◽  
Matthew G Williamson ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Goblet Cell ◽  
House Dust ◽  
House Dust Mite ◽  
Inflammatory Responses ◽  
Lymphoid Cells ◽  
Antibody Treatment ◽  
Dust Mite ◽  
Group 2 ◽  
Goblet Cell Metaplasia

Abstract Background: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group-2-innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. Results: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. Conclusions: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.

scholarly journals Inhibition of β-Catenin/CREB Binding Protein Signaling Attenuates House Dust Mite-Induced Goblet Cell Metaplasia in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Virinchi N. S. Kuchibhotla ◽  
Malcolm R. Starkey ◽  
Andrew T. Reid ◽  
Irene H. Heijink ◽  
Martijn C. Nawijn ◽  
...  
Keyword(s):  
Goblet Cell ◽  
House Dust ◽  
House Dust Mite ◽  
Binding Protein ◽  
Periodic Acid ◽  
Creb Binding Protein ◽  
Mucus Production ◽  
Dust Mite ◽  
Epithelial Junctions ◽  
Goblet Cell Metaplasia

Excessive mucus production is a major feature of allergic asthma. Disruption of epithelial junctions by allergens such as house dust mite (HDM) results in the activation of β-catenin signaling, which has been reported to stimulate goblet cell differentiation. β-catenin interacts with various co-activators including CREB binding protein (CBP) and p300, thereby regulating the expression of genes involved in cell proliferation and differentiation, respectively. We specifically investigated the role of the β-catenin/CBP signaling pathway in goblet cell metaplasia in a HDM-induced allergic airway disease model in mice using ICG-001, a small molecule inhibitor that blocks the binding of CBP to β-catenin. Female 6- 8-week-old BALB/c mice were sensitized to HDM/saline on days 0, 1, and 2, followed by intranasal challenge with HDM/saline with or without subcutaneous ICG-001/vehicle treatment from days 14 to 17, and samples harvested 24 h after the last challenge/treatment. Differential inflammatory cells in bronchoalveolar lavage (BAL) fluid were enumerated. Alcian blue (AB)/Periodic acid–Schiff (PAS) staining was used to identify goblet cells/mucus production, and airway hyperresponsiveness (AHR) was assessed using invasive plethysmography. Exposure to HDM induced airway inflammation, goblet cell metaplasia and increased AHR, with increased airway resistance in response to the non-specific spasmogen methacholine. Inhibition of the β-catenin/CBP pathway using treatment with ICG-001 significantly attenuated the HDM-induced goblet cell metaplasia and infiltration of macrophages, but had no effect on eosinophils, neutrophils, lymphocytes or AHR. Increased β-catenin/CBP signaling may promote HDM-induced goblet cell metaplasia in mice.

scholarly journals Allergin-1 Immunoreceptor Suppresses House Dust Mite–Induced Allergic Airway Inflammation

2020 ◽  
Vol 204 (4) ◽  
pp. 753-762 ◽  
Author(s):  
Haruka Miki ◽  
Satoko Tahara-Hanaoka ◽  
Mariana Silva Almeida ◽  
Kaori Hitomi ◽  
Shohei Shibagaki ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
House Dust ◽  
House Dust Mite ◽  
Allergic Airway Inflammation ◽  
Dust Mite

scholarly journals IL-22 induces Reg3γ and inhibits allergic inflammation in house dust mite–induced asthma models

2017 ◽  
Vol 214 (10) ◽  
pp. 3037-3050 ◽  
Author(s):  
Takashi Ito ◽  
Koichi Hirose ◽  
Aiko Saku ◽  
Kenta Kono ◽  
Hiroaki Takatori ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Inflammation ◽  
House Dust ◽  
House Dust Mite ◽  
Cytokine Production ◽  
Allergic Airway Inflammation ◽  
Lung Epithelial Cells ◽  
Intratracheal Administration ◽  
Lung Epithelial ◽  
Dust Mite

Previous studies have shown that IL-22, one of the Th17 cell–related cytokines, plays multiple roles in regulating allergic airway inflammation caused by antigen-specific Th2 cells; however, the underlying mechanism remains unclear. Here, we show that allergic airway inflammation and Th2 and Th17 cytokine production upon intratracheal administration of house dust mite (HDM) extract, a representative allergen, were exacerbated in IL-22-deficient mice. We also found that IL-22 induces Reg3γ production from lung epithelial cells through STAT3 activation and that neutralization of Reg3γ significantly exacerbates HDM-induced eosinophilic airway inflammation and Th2 cytokine induction. Moreover, exostatin-like 3 (EXTL3), a functional Reg3γ binding protein, is expressed in lung epithelial cells, and intratracheal administration of recombinant Reg3γ suppresses HDM-induced thymic stromal lymphopoietin and IL-33 expression and accumulation of type 2 innate lymphoid cells in the lung. Collectively, these results suggest that IL-22 induces Reg3γ production from lung epithelial cells and inhibits the development of HDM-induced allergic airway inflammation, possibly by inhibiting cytokine production from lung epithelial cells.

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